6-deoxyanthracyclines

ABSTRACT

A compound of the formula ##STR1## wherein R 1  represents a hydrogen atom or a hydroxy group, one of R 2  and R 3  represents a hydrogen atom, the other of R 2  and R 3  represents a hydrogen atom or a hydroxy group and X is a hydrogen atom or a trifluoro acetyl group. The N-trifluoroacetyl 7S:9S and 7R:9R derivatives of the α-glycosides of formula XV can be separated by chromatography on silica gel to obtain, after mild alkaline hydrolysis the wanted 7S:9S α-glycosides (R 1  =H) as free bases and can eventually be transformed into their corresponding doxorubicin derivatives (R 1  =OH) by known procedures.

This is a division of application Ser. No. 06/622,177, filed on June 19,1984, now U.S. Pat. No. 4,939,282.

DESCRIPTION

The invention relates to a process for the preparation of6-deoxy-anthracyclinones, to certain of the 6-deoxyanthracyclinones, tocertain anthracycline glycosides prepared from them, to thoseanthracyclic glycosides in pharmaceutical compositions and to thepreparation of those anthracycline glycosides.

The invention provides a process for the preparation of6-deoxyanthracyclinones having the general formula I ##STR2## wherein Rrepresents a hydrogen atom, a hydroxy group or a lower alkoxy group. Theprocess, which is illustrated in the following reaction scheme,comprises

(i) acetylating dimethyl 1,2,3,6-tetrahydro-phthalate (II) by treatmentwith acetic anhydride in the presence of tin tetrachloride, followed bytreatment with a mild base or a mild acid

(ii) reacting the resultant dimethyl1,2,3,6-tetrahydro-4-acetyl-phthalate (III) with tosylhydrazine,

(iii) reducing the resultant dimethyl1,2,3,6-tetrahydro-4-(1-tosylhydrazone-ethyl)-phthalate (IV) withcatechol borane and subsequently re-arranging the double bond from anendocyclic to an exocyclic position in the presence of sodium acetate,

(iv) oxidizing the resultant1,2-di-(methoxycarbonyl)-4-ethylidene-cyclohexane (V) with potassiumpermanganate and treating the resultant α-hydroxy-ketone with ethyleneglycol in the presence of a catalytic amount of p-toluenesulphonic acid

(v) condensing the resultant2-methoxycarbonyl-5-[2-methyl-dioxolane-2-yl]-6-oxa-bicyclo[3,2,1]octan-7-one(VI) with a compound of the general formula VIII wherein R is as abovedefined (obtained by the action of an alkyllithium on a compound of thegeneral formula VII wherein R is as above defined),

(vi) opening the lactone ring and deprotecting the dioxolan protectedketo group in the resultant compound of the general formula IX wherein Ris as above defined by methanolysis,

(vii) reducing the keto groups of the resultant compound of the generalformula X wherein R is as above defined by treatment with apyridine-borane complex in the presence of trifluoroacetic acid andconverting the methoxycarbonyl group to a benzyloxycarbonyl group bytreatment with phenyldiazomethane,

(viii) esterifying the hydroxy groups and deesterifying thebenzyloxycarbonyl group in the resultant compound of the general formulaXI wherein R is as above defined by treatment with acetic anhydride inpyridine in the presence of 4-dimethylamino-pyridine followed byrefluxing with cyclohexane in the presence of a palladium-on-carboncatalyst,

(ix) cyclizing the resulting compound of the general formula XII whereinR' represents a hydrogen atom, an acetoxy group or a lower alkoxy groupby treatment with a mixture of trifluoroacetic anhydride andtrifluoroacetic acid, and hydrolyzing the acetoxy groups with sodiummethylate,

(x) oxidizing the 1-hydroxyethyl group of the resultant compound of thegeneral formula XIII wherein R is as above defined with silvercarbonate, and oxidatively demethylating the resultant compound withaluminum trichloride in nitrobenzene, and

(xi) protecting the 13-keto group of the resultant compound of thegeneral formula XIV by treatment with ethylene glycol, brominating theresultant compound at C-7 by treatment in the presence of2,2'-azo-bis(isobutyronitrile) with bromine or N-bromosuccinimide, andhydrolysing the 7-bromo and 13-ketal groups. ##STR3##

The starting compounds for the process according to the invention areknown. 2-Bromo-1,4,5-trimethoxy-naphthalene (VII, R═OCH₃) was describedby R. L. Haman, R. B. Barber and H. Rapoport, J. Org. Chem., 44, 2153(1979). The coupling reaction between the compounds VIII and VI proceedsregioselectively in high yield to give the key intermediate IX. Theorganometallic species affects only the carbonyl group of the methylester and not that of the lactone.

Step (xi) may be performed according to the method described by C. M.Wong et al., Can J. Chem., 51, 446 (1973), that is by bromination withbromine in the presence of 2,2'-azo-bis(isobutyronitrile) followed byhydrolysis of the 7-bromo-derivative and removal of the ketal group byacid treatment, or alternatively by bromination with N-bromo-succinimidein the presence of 2,2'-azo-bis(isobutyronitrile), by irradiation,treatment with silver acetate, hydrolysis of the ketal by acidictreatment and finally hydrolysis of the acetate with soduim methoxide.

The optical resolution of the compound IX may be carried out by theconventional method of conversion to diastereoisomeric derivatives usinga chiral resolving agent. Resolution at this point enable(+)-4-demethoxy-6-deoxy-4- (R-substituted)-daunomycinones I to beobtained. The 6-deoxyanthracyclinones I, except that in which Rrepresents a hydrogen atom, are novel and are included within the scopeof the invention. 4-Demethoxy-6-deoxydaunomycinone, prepared by adifferent process, was described in our British Patent Specification No.2100257. The present process is more efficient and more amenable tolarge scale production than the previous described process.

The invention also provides anthracyline glycosides having the generalformula XV ##STR4## wherein R₁ represents a hydrogen atom or a hydroxygroup, one of R₂ and R₃ represents a hydrogen atom, the other of R₂ andR₃ represents a hydrogen atom or a hydroxy group, and X represents ahydrogen atom or a trifluoroacetyl group, with the proviso that if Xrepresents a trifluoroacetyl group than R₁ represents a hydrogen atom.These compounds may be named as follows:

XVa: R₁ =R₃ =H, R₂ =OH, X=COCF₃,4-demethyl-6-deoxy-N-trifluoroacetyl-daunorubicin.

XVb: R₁ =R₃ =H, R₂ =OH, X=H, 4-demethyl-6-deoxy-daunorubicin.

XVc: R₁ =R₂ =OH, R₃ =H, X=H, 4-demethyl-6-deoxy-doxorubicin.

XVd: R₁ =R₂ =H, R₃ =OH, X=COCF₃,4-demethyl-6-deoxy-N-trifluoroacetyl-4'-epi-daunorubicin

XVe: R₁ =R₂ =H, R₃ =OH, X=H, 4-demethyl-6-deoxy-4'-epi-daunorubicin

XVf: R₁ =R₃ =OH, R₂ =H, X=H, 4-demethyl-6-deoxy-4'-epi-doxorubicin

XVg: R₁ =R₂ =R₃ =H, X=COCF₃,4-demethyl-6,4'-dideoxy-N-trifluoroacetyl-daunorubicin

XVh: R₁ =R₂ =R₃ =X=H, 4-demethyl-6,4'-dideoxy-daunorubicin

XVi: R₁ =OH, R₂ =R₃ =X=H, 4-demethyl-6,4'deoxy-doxorubicin.

These authracycline glycosides may be prepared from4-demethyl-6-dexoy-daunomycinone (I, R═OH) by condensation thereof witha protected halosugar having the general formula XVI ##STR5## whereinone of R₂ and R₃ represents a hydrogen atom and the other R₂ and R₃represents a hydrogen atom or a trifluoroacetoxy group, and Halrepresents a halogen atom, preferably a chlorine atom. This condensationproceeds in the presence of silver trifluoromethane sulphonate accordingto the method described in U.S. Pat. No. 4,107,423, giving an easilyseparable mixture of the 7S: 9S and 7R:9R O-trifluoroacetyl protectedderivatives of the α-glycosides. XVa, XVd and XVg according to thehalosugar XVI selected for the reaction.

The O-trifluoroacetyl group may be removed by methanolysis to give thecompounds XVa, XVd and XVg which by mild alkaline hydrolysis can beconverted to the glycosides XVb, XVe and XVh respectively. These, by14-bromination and treatment with aqueous sodium formate in accordancewith the method described in U.S. Pat. No. 3,803,124, give thecorresponding doxorubicin derivatives XVc, XVf and XVi. These processesare within the scope of the invention.

The anthracycline glycosides XV have anti-tumor properties andaccordingly the invention additionally provides a pharmaceuticalcomposition comprising an anthracycline glycoside having the generalformula XV or a pharmaceutically acceptable salt of such a glycoside inwhich X represents a hydrogen atom in admixture with a pharmaceuticallyacceptable diluent or carrier.

The invention is illustrated by the following Examples.

EXAMPLE 1 Dimethyl 1,2,3,6-tetrahydro-4-acetyl-phthalate (III)

10 g dimethyl 1,2,3,6-tetrahydro-phthalate (II) was treated at -5° C.with 25 ml of acetic anhydride in the presence of 9 ml of tintetrachloride. The reaction mixture was poured into iced water andextracted with diethyl ether. The organic phase was washed with asaturated aqueous solution of sodium bicarbonate and then with water,and was then evaporated to dryness under vacuum. The obtained oil wasdissolved in benzene, treated with a methanolic solution of hydrogenchloride. The solution was evaporated to dryness and the residue waspurified by chromatography on column of silica gel to give 9 g of thetitle compound in 75% overall yield. mass spectrum: m/z 240 (M⁺.)

Ir (KBr): 1720 cm⁻¹ (C═O of ester); 1660 cm⁻¹ (C═O of α,β unsaturatedketone).

PMR (CDCl₃): inter alia δ 2.33 (s, COCH₃), 3.70 (s, --COOCH₃) and 6.91(m, HC═C).

EXAMPLE 2 1,2-Di-(methoxycarbonyl)-4-ethylidene-cyclohexane (V)

17 g of dimethyl 1,2,3,6-tetrahydro-4-acetyl-phthalate, prepared asdescribed in Example 1, was refluxed in anhydrous ethanol with 14.6 g oftosylhydrazine. After removal of the solvent, 24 g of dimethyl1,2,3,6-tetrahydro-4-(1-tosylhydraaono-ethyl)-phthalate (IV)crystallized from water m.p. 162°-163° C. m/z 408 (M⁺.). This compoundwas dissolved in chloroform, and treated at 0° C. with 14 ml of catecholborane. Sodium acetate was added to the reaction mixture, which was thenrefluxed. After washing with water, the solvent was evaporated off andthe residue was purified by chromatography on a column of silica gelgiving 10 g of the title compound (yield 80%): m/z 226 (M⁺.); PMR(CDCl₃): inter alia δ 1.6 (d, J=8 Hz, CH₃ --CH═), 5.3 (q, J=8 Hz, CH₃--CH═).

EXAMPLE 32-Methoxycarbonyl-5-(2-methyldioxolan-2-yl)-6-oxabicyclo[3,2,1]octan-7-one(VI)

8 g of 1,2-di-(methoxycarbonyl)-4-ethylidene-cyclohexane, prepared asdescribed in Example 2, was dissolved in aqueous acetone containing 4.8ml of acetic acid. An aqueous solution of potassium permanganate wasadded, and the mixture was allowed to stand for 60 minutes at roomtemperature. The excess oxidant was then destroyed and the reactionmixture, diluted with water, was extracted with ethyl acetate. Theorganic phase, washed with water and dried over anhydrous sodiumsulphate, was evaporated to dryness under vacuum. The residue (9 g) wasdissolved in benzene and refluxed for 60 minutes in the presence of acatalytic amount of p-toluenesulphonic acid. 4 ml of ethylene glycol wasadded and the reaction mixture was refluxed for a further 2 hours. Afterconventional work-up, the residue, obtained by evaporating off thesolvent, was purified by chromatography on a column of silica gel usingas eluent a toluene:acetone mixture (15:1 by volume). 3.0 g of the titlecompound was isolated (yield 33%): m.p. 69°-71° C.; m/z 271 (MH⁺.).

IR (KBr): 1790 cm⁻¹ (C═O five membered ring lactone) 1735 cm⁻¹ (C═Oester); 1720 cm⁻¹ (C═O ketone).

PMR (CDCl₃): inter alia 1.25 (s, CH₃), 3.65 (s, COOCH₃), and 3.9 (s,--O--CH₂ --CH₂ --O--).

EXAMPLE 42-(1,4,5-Trimethoxy-3-naphthylcarbonyl)-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo[3,2,1]octan-7-one(IX, R=OCH₃)

7 ml of a 1.65M hexane solution of n-butyllithium was dissolved in 30 mlof anhydrous tetrahydrofuran. To the solution was added at -78° C. asolution of 3.3 g of 1,4,5-trimethoxy-3bromo-naphthalene (VI, R=OCH₃) in30 ml of anhydrous tetrahydrofuran. 2.5 g of2-methoxycarbonyl-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo[3,2,1]-octan-7-one,prepared as described in Example 3, was dissolved in 50 ml of anhydroustetrahydrofuran and added to the reaction mixture. The reaction mixturewas stood for 1 hour at -78° C. and then quenched with acetic acid. Thesolvent was removed in vacuo. The residue was purified by silica gelcolumn chromatography, giving 3 g (73% yield) of the title compound. m/z456 (M⁺.).

IR (KBr): 1775 cm⁻¹ (C═O five membered ring lactone), 1680 cm⁻¹ (C═Obenzylic ketone).

PMR (CDCl₃): inter alia 1.3 (s, CH₃), 3.75 (s, OCH₃), 3.95-4.05 (m, twoOCH₃ and --O--CH₂ --CH₂ --O--), 6.8 (s, aromatic CH) and 6.8-8.1 (m,three H).

EXAMPLE 51-(1,4,5-trimethoxy-3-naphthylmethyl-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxy-cyclohexane(XI, R=OCH₃)

1.6 g of2-(1,4,5-trimethoxy-2-naphthylcarbonyl)-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo[3,2,1]octan-7-one,prepared as described in Example 4, was dissolved in methanol andtreated at room temperature for 1 hour with a 1N solution of hydrogenchloride in anhydrous methanol. After evaporating off the solvent, therewas obtained in almost quantitative yield 1.5 g of1-1,4,5-trimethoxy-3-naphthylcarbonyl)-2-methoxycarbonyl-4-acetyl-4-hydroxy-cyclohexane(X, R=OCH₃). m/z 444 (M⁺.); IR (film): 3460 cm⁻¹ (OH), 1730 cm⁻¹ (C═Oester, 1710 cm⁻¹ (C═O ketone) and 1665 cm⁻¹ (C═O benzylic ketone). PMR(CDCl₃): inter alia 2.3 (s, CH₃ CO), 3.75-4.05 (s, four OCH₃), 6.8 (s,aromatic H) and 6.85-8.0 (m, three aromatic H). 1.5 g of this compoundwas dissolved in 15 mo of trifluoroacetic acid and refluxed with 1.4 mlof pyridine-borane complex. After removal of the solvent, the residuewas treated with a 10% aqueous solution of sodium hydroxide. After mildacidification the free acid was extracted with ethyl acetate. Thesolvent was evaporated off and the residue was directly treated with anethereal solution of phenyldiazomethane to give the title product. Thiswas purified by chromatography: m/z 508 (M⁺.); PMR (CDCl₃): inter alia1.25 (d, CH₃ --CH), 3.70-3.95 (s, three OCH₃), 5.15 (d, CH₂ Ph) and6.4-8.1 (m, nine aromatic H).

EXAMPLE 61,2,3,4,4a,5,12,12a-Octahydro-2-(1-hydroxyethyl)-2-hydroxy-6,7,11-trimethoxy-12-oxonaphthacene(XIII, R═OCH₃)

0.48 g of1-(1,4,5-trimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxy-cyclohexane,prepared as described in Example 5, was treated with acetic anhydrideand pyridine in the presence of 4-dimethylamino-pyridine. After a nightat room temperature the reaction mixture was poured into iced water andextracted with ethyl acetate. The organic layer was washed with waterand concentrated. The crude product was dissolved in methanol andrefluxed with cyclohexene in the presence of 10% by weightpalladium-on-carbon. The catalyst was then filtered off and thesolution, concentrated to a small volume, was treated at 0° C. for 60minutes with trifluoroacetic anhydride and trifluoroacetic acid. Thenthe solution was diluted with ethyl acetate, washed with an aqueoussaturated solution of sodium bicarbonate and with water, dried andconcentrated to dryness under vacuum. The residue was dissolved inmethanol in the presence of catalytic amount of sodium methylate. Afterconventional work-up and purification by chromatography 0.18 g of thetitle compound was obtained (yield 49%): m/z 400 (M⁺.); IR (KBr): 3450cm⁻¹ (OH), 1675 cm⁻¹ (C═O benzylic ketone); PMR (CDCl₃): inter alia δ(1.2 (d, CH₃ --CH), 3.7-3.9 (s, three OCH₃) and 6.4-8.0 (m, threearomatic hydrogen).

EXAMPLE 71,2,3,4,4a,5,12,12a-Octahydro-2-acetyl-2-hydroxy-6,7,11-trimethoxy-12-oxo-naphthacene

0.8 g of silver carbonate was added to a solution in benzene of 0.09 gof1,2,3,4,4a5,12,12a-Octrahydro-2-(1-hydroxyethyl)-2-hydroxy-6,7,11-trimethoxy-12-oxo-naphthacene,prepared as described in Example 6, and the mixture was refluxed. Afterfiltering off the solid and evaporating off the solvent in vacuo, 0.08 gof the title compound was obtained (90% yield).

IR (KBr): 3360 cm⁻¹ (OH), 1705 cm⁻¹ (C═O ketone), 1680 cm⁻¹ (C═O,benzylic ketone).

PMR (CDCl₃): inter alia δ 2.2 (s, CH₃ CO), 3.65-3.90 (s, three OCH₃).

EXAMPLE 8 6,7-Dideoxycarminomycinone (XIV, R═OH)

0.06 g of1,2,3,4,4a,5,12,12a-octahydro-2-acetyl-2-hydroxy-6,7,11-trimethoxy-12-oxonaphthacene,prepared as described in Example 7, was dissolved in nitrobenzene andtreated with 0.12 g of aluminium trichloride. The mixture was kept at70° C. until no more starting material was detectable. The reactionmixture was poured into an aqueous saturated solution of oxalic acid andextracted with ethyl acetate. The organic phase was separated, washedwith water, dried and evaporated to dryness. The residue, purified on acolumn of silica gel, afforded pure 6,7-dideoxycarminomycinone, yield40%: m/z 352 (M⁺.); IR (KBr): 3420 cm⁻¹ (OH), 1705 cm⁻¹ (C═O ketone) and1625 cm⁻¹ (C═O, chelated quinone). PMR (CDCl₃): inter alia δ 1.7-2.2 (m,CH₂), 2.3 (s, CH₃ CO), 2.8-3.2 (m, two benzylic CH₂), 7.0-7.9 (m, fouraromatic H), 12.6 (s, phenolic OH) and 12.9 (s, phenolic OH).

EXAMPLE 9 6-Deoxycarminomycinone (I: R═OH)

A solution of 6,7-dideoxycarminomycinone, prepared as described inExample 8, in benzene was treated at refluxing temperature for 4 hourswith 1.2 ml of ethylene glycol in the presence of a catalytic amount ofp-toluenesulphonic acid, affording the corresponding 13-ketalderivative. This compound was dissolved in carbon tetrachloride andtreated with 2 ml of a solution of 3.2 g of bromine in 32 ml of carbontetrachloride at 45° C. for 6 hours in the presence of2,2'-azo-bis(isobutyronitrile). The cooled reaction mixture wasextracted with 1N aqueous sodium hydroxide and the coloured aqueousphase was adjusted to pH 8.5 and extracted with chloroform. The organicextracts, evaporated to dryness, afforded6-deoxy-13-ketal-carminomycinone. This was dissolved in acetonecontaining hydrogen chloride (300 ml of a 0.25N solution) and kept atroom temperature for 3 hours in order to hydrolyze the ketal group. Thedesired 6-deoxycarminomycinone was obtained.

Alternative Method

A solution of 50 mg (0.125 mmol) of the 13-ketal derivative of6,7-dideoxycarminomycinone in 20 ml of carbon tetrachloride containing0.14 mmol of N-bromo-succinimide and 0.06 mmol of2,2'-azo-bis(isobutyronitrile) was refluxed for 25 minutes. The residue,obtained by evaporating off the solvent under vacuum was dissolved inglacial acetic acid and treated with 80 mg of silver acetate. Themixture was stirred at room temperature for five hours. The solvent wasevaporated off, and the residue was dissolved in ethyl acetate andfiltered. The filtrate was washed with a saturated of sodium bicarbonateand with water, dried and concentrated. The residue was dissolved inaqueous acetic (90% by volume) at 0° C. and stirred for 90 minutes.After solvent removal, the residue was dissolved in methanol, sodiummethoxide was added and the mixture was stirred for 90 minutes. Afterneutralization, extraction and washing with water, the residue waspurified by flash chromatography with methylene dichloride:acetone (16:1by volume). The desired 6-deoxycarminomycinome was obtained in 34%overall yield. m/z 368 (M⁺.), m.p. 211°-213° C., TLC on Kieselgel plates(Merck F₂₅₄) using as eluent solvent toluene:acetone 4:1 by volume,Rf=0.3. PMR (200 MHz, CDCl₃): δ 2.1-2.3 (m, 2H, H-8), 2.3 (s, 3H,--COCH₃), 2.7-3.1 (q, 2H, H-10), 4.1 (d, 1H, OH-7), 4.4 (s, 1H, OH-9),4.8 (d, 1H, H-7), 7.3 (d, 1H, H-3), 7.7 (t, 1H, H-2), 7.8 (d, 1H, H-1),8.1 (s, 1H, H-6), 12.8 (s, 1H, OH-4), 13.2 (s, 1H, OH-11).

EXAMPLE 102-(1,4-Dimethoxy-3-naphthylcarbonyl)-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo[3,2,1]octan-7-one(IX, R═H)

Following the method described in Example 4, a solution of 3.2 g of1,4-dimethoxy-3-bromo-naphthalene in anhydrous tetrahydrofuran wastreated at -78° C. with n-butyllithium and then added to a solution inanhydrous tetrahydrofuran of 2.7 g of the compound prepared in Example3. After silica gel column purification 2.8 g of the title compound wasobtained (65% yield) m/z 426 (M⁺.): IR (film): 1780 cm⁻¹ (C═O, fivemembered ring lactone), 1670 cm⁻¹ (C═O, benzylic ketone); PMR (CDCl₃):inter alia: δ 1.4 (s, CH₃), 3.85 (s, two OCH₃), 3.9 (s, --O--CH₂ --CH₂--O--), 6.9 (s, aromatic H) and 7.4-8.4 (m, four aromatic H).

EXAMPLE 111-(1,4-dimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxy-cyclohexane(XI, R═H)

Operating as described in Example 5, the treatment of2-(1,4-dimethoxy-3-naphthylcarbon)-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo[3,2,1]octan-7-one,prepared as described in Example 10, with a solution of hydrogenchloride in methanol afforded1-(1,4-dimethoxy-3-naphthylcarbonyl)-2-methoxycarbonyl-4-acetyl-4-hydroxy-cyclohexane(X, R=H) in almost quantitative yield. m/z 414 (M⁺.): IR (film): 3460cm⁻¹ (OH), 1730 cm⁻¹ (C═O ester), 1710 cm⁻¹ (C═O ketone) and 1670 cm⁻¹(C═O, benzylic ketone). PMR (CDCl₃): inter alia: δ 2.3 (s, CH₃ CO),2.9-3.6 (m, two H), 3.7-3.9 (s, three OCH₃), 6.9 (s, aromatic H) and7.4-8.4 (m, four aromatic H).

1 g of this compound, by reduction with pyridine-borane complex, basictreatment and finally esterification with phenyldiazomethane wasconverted to the title compound (0.7 g, overall yield 63%). m/z 478(M⁺.): IR (film): 3450 cm⁻¹ (OH), 1725 cm⁻¹ (C═O, ester). PMR (CDCl₃):inter alia δ 1.3 (d, J=4 Hz, CH₃ --CH), 3.85-3.9 (s, two OCH₃), 5.1 (s,CH₂ -benzylic), 6.6 (s, aromatic H) and 7.2-8.4 (m, nine aromatichydrogens).

EXAMPLE 121,2,3,4,4a,5,12,12a-Octahydro-2-(1-hydroxyethyl)-2-hydroxy-6,11-dimethoxy-12-oxo-naphthacene(XIII, R=H)

Operation as described in Example 6, 0.44 g of1-(1,4-dimethoxy-3-naphthylmethyl)-2-benzyloxycarbonyl-4-(1-hydroxyethyl)-4-hydroxyl-cyclohexane,prepared as described in Example 11, was treated with acetic anhydridein presence of 4-dimethylamino-pyridine and pyridine. The correspondingacetate was treated with cyclohexene in the presence of 10% by weightpalladium-on-carbon in order to remove the benzyl group. The acid wascyclized by treatment with a mixture of trifluoroacetic anhydride andtrifluoroacetic acid at 0° C. Finally the removal of the acetylO-protecting groups by treatment with sodium methylate afforded. afterpurification by chromatography on a silica gel column, 0.225 g of thetitle compound (overall yield 66%); IR (film): 3450 cm⁻¹ (OH), 1675 cm⁻¹(C═O, benzylic ketone). PMR (CDCl₃): inter alia δ 1.3 (d, J=4 Hz, CH₃--CH), 1.6-3.5 (m, 3H), 3.85 (s, OCH₃), 3.90 (s, OCH₃), 7.2-8.4 (m, fouraromatic H).

EXAMPLE 131,2,3,4,4a,5,12,12a-Octahydro-2-acetyl-2-hydroxy-6,11-dimethoxy-12-oxo-naphthacene

0.1 g of1,2,3,4,4a,5,12,12a-octahydro-2-(1-hydroxyethyl)-2-hydroxy-6,11-dimethoxy-12-oxo-naphthacene,prepared as described in Example 12, in benzene was treated with 1 g ofsilver carbonate at refluxing temperature. After filtering off theinorganic solids and removing the solvent, 0.1 g of the title productwas obtained.

IR (film): 3460 cm⁻¹ (OH), 1710 cm⁻¹ (C═O ketone), 1680 cm⁻¹ (C═Obenzylic ketone).

PMR (CDCl₃): inter alia δ 2.4 (s, CH₃ CO), 3.85 (s, OCH₃), 3.90 (s,OCH₃), 7.2-8.4 (m, four aromatic H).

EXAMPLE 14 4-Demethoxy-6,7-dideoxydaunomycinone (XIV, R=H)

Operating as described in Example 8, a solution of 0.1 g of1,2,3,4,4a,5,12,12a-octahydro-2-acetyl-2-hydroxy-6,11-dimethoxy-12-oxo-naphthacene,prepared as described in Example 13, in 3 ml of nitrobenzene was treatedwith 0.25 g of aluminium trichloride overnight at room temperature.After silica gel column chromatography, 0.055 g (63% yield) of the titlecompound was obtained. m.p. 203°-204° C.

EXAMPLE 15 6-Deoxy-4-demethyl daunorubicin (XVb)

90 mg (0.24 mmol) of racemic 6-deoxy-carminomycinone, prepared asdescribed in Example 9 was dissolved in anhydrous dichloromethane andthe solution was cooled to 5°-10° C. A solution of 2.4 mg (0.6 mmol) of1-chloro-N,O-ditrifluoroacetyl-daunosamine, prepared following theprocedure described in Cancer Chemotherapy Reports, Part 3, Vol. 6, No.2, p. 123, in diethyl ether and a solution of 154 mg (0.6 mmol) ofsilver trifluoromethanesulphonate in dichloromethane were addedsimultaneously and rapidly under vigorous stirring.

After 5 minutes, a further 0.3 mmol of the halosugar and 0.3 mmol ofsilver trifluoromethane sulphonate were added. After 5 minutes, thereaction was quenched with collidine. The mixture was filtered, washedwith a saturated aqueous solution of sodium bicarbonate and with water,dried and concentrated under vacuum. The reddish oil obtained wasdiluted with 100 ml of methanol and allowed to stand overnight at roomtemperature to remove the O-trifluoroacetyl group. The resulting crudeproduct was purified by flash chromatography on silica gel withdichloromethane:methanol:acetone 20:1:1 by volume to afford theanthracycline α-glycosides XVa. 7S:9S, 20 mg, m.p. 210°-212° C.

TLC on kieselgel plates (Merck F₂₅₄), using as eluentmethylene-dichloride:acetone 4:1 by volume, Rf=0.27. m/z 593 (M⁺.).

PMP (2000 MHz, CDCl₃): inter alia δ 1.44 (d, J=6.6 Hz, 3H, CH₃ -5'),2.42 (s, 3H, COCH₃), 3.25-3.05 (two d, J=19 Hz, 2H, H-10), 4.22 (s, 1H,OH-9), 5.01 (t, J=3.6 Hz, 1H, H-7), 5.20 (t, J=2.7 Hz, 1H, H-1'), 6.66(bd, J=9 Hz, 1H, NH), 7.80 (s, 1H, H-6), 12.62 (s, 1H, OH-4), 13.06 (s,1H, OH-11); m/z 593 (M⁺.), 7R:9R 25 mg, m.p. 174°-178° C.

TLC on kieselgel plates (Merck F₂₅₄) using as eluent methylenedichloride:acetone 4:1 by volume, Rf=0.23. m/z 593 (M⁺.).

PMR (200 MHz, CDCl₃): inter alia δ 1.44 (d, J=6.5 Hz, 3H, CH₃ -5'), 2,41(s, 3H, COCH₃), 2.96 (d, J=19 Hz, 1H, H-10 ax), 3.30 (dd, J=1, 19 Hz,1H, H-10 eq), 4.25 (x, 1H, OH-9), 5.07 (t, J=3.3 Hz, 1H, H-7), 5.27 (t,J=1.8 Hz, 1H, H-1'), 6.64 (bd, J=9 Hz, 1H, NH), 7.74 (s, 1H, H-6), 12.66(s, 1H, OH-4), 13.10 (s, 1H, OH-11).

Mild alkaline hydrolysis of XVa removes the N-trifluoroacetyl group togive the title compound in quantitative yield. TLC on kieselgel plates(Merck F₂₅₄) using as eluent methylene dichloride:methanol:aceticacid:water 80:20:7:3 by volume, Rf 0.47.

EXAMPLE 16 6-deoxy-4-demethyl-doxorubicin (XVc)

A solution of 6-deoxy-4-demethyl-daunorubicin prepared as described inExample 15 in a mixture of methanol and dioxane was treated with bromideto form the 14-bromo derivative. Treatment of the 14-bromo derivativewith an aqueous solution of sodium formate at room temperature for 100hours gave 6-deoxy-4-demethyl-doxorubicin.

m.p. 167°-170° C.

Chromatography on TLC (Merck F254) using solvent system CH₂ Cl₂:MeOH:AcOH:H₂ O (8:2:0.7:0.3 v/v) Rf=0.47.

What we claim is:
 1. 4-demethyl-6deoxy-daunomycinone. 2.6-deoxy-daunomycinone.